Publications by Year: 1989

Sharpe AH, Hunter JJ, Ruprecht RM, Jaenisch R. Maternal transmission of retroviral disease and strategies for preventing infection of the neonate. J Virol. 1989;63 (3) :1049-53.Abstract
Moloney murine leukemia virus is efficiently transmitted from viremic mothers to offspring, primarily via virus-containing milk. To determine the level in the infectious process at which an antiviral agent can interfere most effectively with perinatal viral transmission, we examined the effect of the drug 3'-azido-3'-deoxythymidine (AZT) on transmission of Moloney murine leukemia virus from viremic mothers to offspring. Although AZT treatment did not affect the titer of virus in milk, it did suppress the development of viremia in all offspring. AZT, however, did not prevent transmission of virus from viremic mothers to 25% of the offspring, but did lead to a marked reduction in virus load in these infected mice. These results provide evidence for effective antiretroviral therapy during gestation and in the perinatal period and are of potential significance for the management of maternal transmission of human retroviruses.
Compere SJ, Baldacci P, Sharpe AH, Thompson T, Land H, Jaenisch R. The ras and myc oncogenes cooperate in tumor induction in many tissues when introduced into midgestation mouse embryos by retroviral vectors. Proc Natl Acad Sci U S A. 1989;86 (7) :2224-8.Abstract
Midgestation embryos were infected with replication-defective retroviral vectors that either transduced the myc oncogene, the ras oncogene, or both oncogenes simultaneously. The myc virus induced tumors in diverse organs at a very low frequency and with a long latency period, while approximately 20% of the mice derived from embryos infected with the ras virus developed tumors in the skin with a latency of 4-8 weeks. In contrast, infection of embryos with the ras/myc double oncogene virus resulted in 27% of the animals developing rapidly growing and malignant tumors in a great variety of tissues after a median latency period of 2-3 weeks. All tumors were of monoclonal origin, as shown by Southern analysis using the provirus as a molecular marker. Our results are consistent with the hypothesis that the ras and myc oncogenes cooperate in transforming cells, but that additional alterations are necessary for realization of the fully malignant phenotype. Our observations also suggest that a much wider range of cell types become targets for malignant transformation when the embryos are exposed to the myc and the ras oncogenes simultaneously than when exposed to the same oncogenes separately. Infection of mouse embryos with vectors carrying different oncogenes or oncogene combinations may be an efficient and rapid method for evaluating the spectrum of cell types at risk for malignant conversion following mutation of a protooncogene to a transforming gene.
Compere SJ, Baldacci PA, Sharpe AH, Jaenisch R. Retroviral transduction of the human c-Ha-ras-1 oncogene into midgestation mouse embryos promotes rapid epithelial hyperplasia. Mol Cell Biol. 1989;9 (1) :6-14.Abstract
Infection of mouse embryos at 8 days of gestation with a replication-defective retrovirus carrying the human c-Ha-ras-1 oncogene led to efficient and rapid induction of hyperplastic lesions. Twenty-four percent of viable off-spring developed abnormal growths after infection with purified virus. The lesions contained a single integrated provirus and produced viral RNA and the Ha-ras oncogene product (p21). The latency period between the time of infection and appearance of the lesions suggested that secondary alterations in addition to activated ras were necessary for neoplasms to develop. The earliest and most abundant growths were cutaneous and appeared from 4 to 36 weeks of age, with a median of 4 weeks of age. A number of subcutaneous lesions also developed over the same time span but at a median of 18 weeks of age. The rapid development of cutaneous lesions in response to transduction of the ras oncogene contrasts with other studies in which adult skin required secondary treatment with promoters prior to ras induction of epithelial hyperplasia. These results demonstrate that infection of midgestation mouse embryos allows rapid analysis of oncogene potency in skin.